HRP20100281A2 - Crystalline forms of palonosetron hydrochloride - Google Patents

Abstract

The present invention provides crystalline forms of palonosetron hydrochloride, methods for their preparation, and pharmaceutical compositions comprising such crystalline forms of palonosetron hydrochloride.

Description

Reference to related applications

The subject application claims the use of the following United States Provisional Patent Application Nos.: 60/853,840, filed Oct. 23, 2006; 60/861,488, filed Nov. 28, 2006; 60/861,847, filed Nov. 29, 2006; 60/899,102, filed Feb. 1, 2007; 60/899,109, filed February 1, 2007; 60/919,615, filed Mar. 20, 2007 and 60/955,679, filed Aug. 14, 2007. The contents of these applications are incorporated herein by reference.

Field of invention

The subject invention is directed to new crystalline forms of palonosetron hydrochloride and to processes for their preparation, and to their pharmaceutical compositions.

State of the art

Palonosetron hydrochloride, 1H-benz[de]isoquinolin-1-one, 2-(3S)-1-azabicyclo[2.2.2]oct-3-yl-2,3,3aS,4,5,6-hexahydro-monohydrochloride , the following formulas:

[image]

is a selective 5HT3-antagonist (prevention against nausea and vomiting induced by chemotherapy). It is marketed as a solution under the name Aloxi® by Hellsinn.

Palonosetron hydrochloride and its preparation were first reported in US Pat. No. 5,202,333. Isolation of palonosetron hydrochloride by crystallization from ethanol has also been reported, yielding palonosetron hydrochloride with a melting point of 296-297°C.

Crystallization of palonosetron hydrochloride is also reported in US Pat. 5,567,818. The procedure involves subjecting 1078.8 g of a solid containing a diastereomeric mixture of 97% 3aS and 3% 3aR to 2-(1-azabicyclo[2.2.2]oC1-3S-yl) 2,3,3a,4,5,6-hexahydro -1H-benz[de]isoquinolin-1-one-hydrochloride by the following procedure: "The diastereomeric mixture ... was dissolved in 29.3 L of isopropanol. The solution was heated to reflux and 1 L of water and 2.5 L of additional of isopropanol. The mixture was distilled to a volume of approximately 16 L, cooled to 20°C over 2 hours, then cooled to 5°C and stirred for approximately 18 hours to give a crystalline precipitate. The precipitate was isolated by filtration and dried under nitrogen or oven vacuum at 68°C."

The appearance of different forms of the solid state (polymorphism) is a property of some molecules and molecular complexes. A single molecule, such as palonosetron hydrochloride, in the above formula can cause different solids to have different physical properties, such as melting point, X-ray diffraction pattern, infrared absorption pattern, and NMR spectrum. Differences in the physical properties of polymorphs result from the orientation and intermolecular interactions of neighboring molecules (complexes) in the bulk of the solid. Accordingly, polymorphs are different solids that share the same molecular formula, which still have different favorable and/or unfavorable physical properties compared to other forms in the polymorph family. One of the most important physical properties of pharmaceutical polymorphs is their solubility in aqueous solution.

The discovery of new polymorphic drug forms increases the repertoire of materials available to the formulation scientist for designing a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics. Therefore, it is necessary to find more crystalline forms of palonosetron hydrochloride.

Thus, there is a need in the art for new crystalline forms of palonosetron hydrochloride and methods for their preparation.

Summary of the invention

In one aspect, the present invention provides a crystalline form of palonosetron hydrochloride, characterized by data selected from the group consisting of: PXRD (Powder X-Ray Diffraction) with reflection peaks at about 13.0, 15.4 and 17.5 ±0.2 degree two-theta, PXRD essentially as shown in Figure 1 and combinations thereof.

In another aspect, the present invention provides a process for the preparation of crystalline palonosetron hydrochloride, characterized by data selected from the group consisting of: PXRD with reflection peaks at about 13.0, 15.4 and 17.5 ± 0.2 degree two-theta, PXRD essentially as shown in Figure 1 and combinations thereof, comprising crystallization of palonosetron hydrochloride having less than 65% palonosetron 3aS palonosetron HCl of the following formula,

[image] .

from a solvent selected from the group consisting of methanol, a mixture of isopropanol and water, and a mixture of methanol, isopropanol and water at a temperature below 55°C.

In another aspect, the present invention provides a crystalline form of palonosetron hydrochloride, characterized by data selected from the group consisting of: PXRD with reflection peaks at about 12.1, 15.8 and 17.3 ± 0.2 degree two-theta, PXRD in be as shown in Figure 2 and combinations thereof.

In another aspect, the present invention provides a process for the preparation of crystalline palonosetron hydrochloride, characterized by data selected from the group consisting of: PXRD with reflection peaks at about 12.1, 15.8 and 17.3 ± 0.2 degree two-theta, PXRD essentially as shown in Figure 2 and combinations thereof, comprising crystallization of palonosetron hydrochloride having at least 96% palonosetron 3aS palonosetron HCl of the following formula,

[image] .

from a mixture of isopropanol and water at a temperature above 55°C.

In yet another aspect, the present invention provides a process for preparing crystalline palonosetron hydrochloride characterized by data selected from the group consisting of: PXRD with reflection peaks at about 12.1, 15.8 and 17.3 ±0.2 degree two-theta, PXRD essentially as shown in Figure 2 and combinations thereof, comprising exposure of crystalline palonosetron hydrochloride characterized by data selected from blackberry consisting of: PXRD with reflection peaks at about 13.0, 15.4 and 17.5 ±0, 2 degrees of two-theta, PXRD essentially as shown in Figure 1, and combinations thereof, relative humidity of 100%.

In yet another aspect, the present invention provides a pharmaceutical composition comprising at least one of the palonosetron hydrochloride crystalline forms of the present invention and a pharmaceutically acceptable excipient.

In one aspect, the present invention provides a process for the preparation of a pharmaceutical composition containing at least one of the crystalline forms of palonosetron hydrochloride of the present invention and a pharmaceutically acceptable excipient.

In one embodiment, the present invention provides pharmaceutical formulations containing at least one of the crystalline forms of palonosetron hydrochloride prepared in accordance with the methods of the present invention, and a pharmaceutically acceptable excipient.

In another embodiment, the subject invention provides a method for preparing pharmaceutical formulations containing at least one of the crystalline forms of palonosetron hydrochloride prepared in accordance with the methods of the subject invention, and a pharmaceutically acceptable excipient.

Short description of the pictures

Figure 1 illustrates an X-ray diffraction pattern of crystalline palonosetron HCl powder characterized by data selected from the group consisting of: PXRD with reflection peaks at about 13.0, 15.8, and 17.5 degree two-theta, PXRD essentially as shown in FIG. 1 and combinations thereof.

Figure 2 illustrates an X-ray diffraction pattern of crystalline palonosetron HCl powder characterized by data selected from the group consisting of: PXRD with reflection peaks at about 12.1, 15.8 and 17.3 degrees two-theta, PXRD as shown in Figure 2 and combinations thereof.

Detailed description of the invention

The present invention provides new crystalline forms of palonosetron hydrochloride (herein referred to as PAL-HCl), processes for their preparation and pharmaceutical compositions thereof.

The present invention provides a crystalline form of PAL-HCl characterized by data selected from the group consisting of: PXRD with reflection peaks at about 13.0, 15.4 and 17.5 ±0.2 degrees two-theta, a PXRD pattern essentially shown in FIG. Figure 1 and combinations thereof.

Said crystalline form can be further characterized by PXRD with peaks at about 7.1, 13.7, 14.2, 16.2, 18.5, 20.0 and 22.1 ± 0.2 degrees two-theta. Said crystalline form of PAL-HCl can also be characterized with a DSC thermogram having an endothermic peak at around 311°C, due to melting.

In addition, the above crystalline form can be characterized by a weight loss of less than 0.1% as measured at a temperature less than or equal to 153°C by TGA (thermogravimetric analysis). Additionally, the above crystalline form is the anhydrous form of PAL-HCl.

Said crystalline form of PAL-HCl has less than 20%, preferably less than 10%, more preferably less than 5% of crystalline palonosetron hydrochloride characterized by data from the group consisting of: PXRD with reflection peaks at about 12.1, 15.8 and 17 ,3 ±0.2 degrees of two-theta, PXRD arrangement essentially as shown in Figure 2 and combinations thereof. Typically, the content of crystalline palonosetron hydrochloride characterized by data selected from the group consisting of: PXRD with reflection peaks at about 12.1, 15.8 and 17.3 ± 0.2 degrees two-theta, a PXRD pattern essentially as shown in Figure 2 and combinations thereof, was measured by wt.-%, preferably as determined by PXRD.

The above crystalline PAL-HCl is prepared by a process comprising crystallization of palonosetron hydrochloride having less than 65% of 3aS palonosetron HCl of the following formula:

[image]

from a solvent selected from the group consisting of methanol, a mixture of isopropanol and water, and a mixture of methanol, isopropanol and water at a temperature below 55°C.

The crystallization process includes obtaining a solution of PAL-HCl having less than 65% 3aS palonosetron HCl in a solvent obtained from the group consisting of methanol, a mixture of isopropanol and water, and a mixture of methanol, isopropanol and water, and precipitation of said crystalline PAL-HCl at a temperature below 55°C.

Suitably, the content of the 3aS palonosetron HCl isomer in palonosetron HCl is about 65% to about 50%. Measurement of the content of the 3aS palonosetron HCl isomer in palonosetron HCl is by % area, conveniently by HPLC.

The above solution is conveniently prepared by a process comprising combining PAL-HCl having less than 65% 3aS Palonosetron HCl and a solvent at a temperature of about 25°C to about reflux to give said solution.

In a suitable embodiment, a solution of PAL-HCl in methanol is obtained by combining PAL-HCl and methanol at a temperature of about 10°C to about 30°C, preferably from about 20°C to about 25°C, more suitable than about 25°C.

In another preferred embodiment, a solution of PAL-HCl in a mixture of IPA and water is obtained by combining PAL-HCl having less than 65% 3aS palonosetron HCl and a mixture of IPA and water at a temperature of at least about 75°C.

In another preferred embodiment, a solution of PAL-HCl in a mixture of methanol, IPA and water is obtained by combining a methanol residue of PAL-HCl having less than 65% 3aS palonosetron HCl with a mixture of IPA and water at a temperature of at least 75°C.

Conveniently, a methanol residue of PAL-HCl having less than 65% 3aS palonosetron HCl can be prepared by a process comprising concentrating a solution of PAL-HCl having less than 65% 3aS palonosetron HCl in methanol to give a concentrated solution, adding IPA or of a mixture of IPA and water to obtain a mixture, concentrating the mixture to obtain the said methanolic residue. This procedure can be repeated.

Conveniently, the solvent ratio in the IPA-water mixture is from about 94:6 to about 97:3, more preferably from about 95:5, or up to about 97:3.

Conveniently, combining PAL-HCl having less than 65% 3aS palonosetron HCl or its methanolic residue with a mixture of IPA and water is carried out at about 75°C to about 90°C, more preferably at about 77°C to about 85°C, even more conveniently at about 77°C to about 80°C, most conveniently at reflux temperature. The reflux temperature can vary according to the total amount of water. In this process of the present invention, water may be present in the solution in a total amount of about 2 to about 6% v/v. The solution obtained in this process of the present invention may contain methanol, IPA and water in a ratio of about 0.5:94.5:5, or up to about 0.1:94.9:5 v/v.

Precipitation can be achieved by cooling the solution, evaporating the solvent, or a combination of both, both of which are carried out at temperatures below 55°C. When the solvent is methanol, precipitation is conveniently achieved by evaporating the solution at a temperature of from about 10°C to about 30°C, more preferably from about 20°C to about 25°C, even more preferably from about 25°C.

When the solvent is a mixture of IPA and water, precipitation is conveniently achieved by cooling the solution to a temperature below about 55°C to obtain a suspension, conveniently to a temperature of about 48-52°C, then the temperature is further lowered to about 0°C, more conveniently to a temperature of 25°C to about 0°C, to obtain a suspension increasing the utilization of regeneration.

The amount of precipitated crystalline product can be increased by a process comprising at least one of the following steps: concentrating the second suspension, and further maintaining the second suspension at such a cooled temperature for a sufficient period of time. Conveniently, the concentration is carried out at a temperature of about 45°C to about 55°C. Suitably, the suspension is further maintained at a temperature of from about 25°C to about 0°C, more preferably from about 10°C to about 0°C. Suitably, the second suspension is maintained for about 10 to about 24 hours, more preferably for about 15 to about 20 hours.

The process for preparing the crystalline PAL-HCl characterized above may further comprise a regeneration process. Crystalline PAL-HCl can be regenerated by any process known to one skilled in the art, such as filtration and/or drying.

The present invention also provides crystalline PAL-HCl characterized by data selected from the group consisting of: PXRD with reflection peaks at about 12.1, 15.8 and 17.3 ±0.2 degrees two-theta, PXRD pattern as essentially shown in Figure 2 and combinations thereof.

This crystalline form can be further characterized by the above PXRD pattern with peaks at about 7.1, 13.8, 14.2, 14.5, 18.5, 20.0 and 30.3 ± 0.2 degrees two-theta.

Said crystalline PAL-HCl can also be further characterized with a DSC thermogram having an endothermic peak at around 313°C due to melting. In addition, the above crystalline PAL-HCl can be characterized by a weight loss of less than about 0.1% as measured at a temperature less than or equal to 152°C by TGA. Additionally, the above crystalline PAL-HCl is the anhydrous form of PAL-HCl.

This crystalline PAL-HCl has less than 20%, preferably less than 10%, more preferably less than 5% of crystalline palonosetron hydrochloride characterized by data selected from the group consisting of: PXRD with reflection peaks at about 13.0, 15.4 and 17 .5 ±0.2 degrees of two-theta, PXRD arrangement essentially as shown in Figure 1 and combinations thereof. Content of crystalline palonosetron hydrochloride characterized by data selected from the group consisting of: PXRD with reflection peaks at about 13.0, 15.4, and 17.5 ± 0.2 degrees two-theta, PXRD pattern substantially as shown in Figure 1 and combinations thereof can be measured by wt.-%, conveniently by PXRD.

Crystalline PAL-HCl with data selected from the group consisting of: PXRD with reflection peaks at about 12.1, 15.8, and 17.3 ±0.2 degrees two-theta, PXRD pattern essentially as shown in Figure 2 and combinations thereof, is prepared by a process comprising crystallizing palonosetron hydrochloride having at least 96% 3aS palonosetron HCl of the following formula,

[image]

from a mixture of isopropanol and water at a temperature above 55°C.

In one embodiment, crystallization is performed by obtaining a solution of PAL-HCl having at least 96% 3aS palonosetron HCl in a mixture containing IPA and water at a temperature above 55°C and precipitating said crystalline PAL-HCl at a temperature of at least about 55°C.

Measurement of the content of the 3aS palonosetron HCl isomer in palonosetron HCl is by % area, conveniently by HPLC.

The solution is obtained by a process comprising mixing PAL-HCl having at least 96% 3aS palonosetron HCl with a mixture containing IPA and water to form a suspension, and heating the suspension to a temperature above 55°C.

The starting PAL-HCl may be a dry solid. The term "dry" in reference to PAL-HCl, as used herein, refers to a solid that does not lose any weight when dried.

It is convenient that the solvent ratio in the IPA-water mixture is about 94:6 to about 98:2, more preferably about 95:5, or up to about 98:2.

Suitably, the suspension is heated to a temperature of at least 75°C, suitably at about 75°C to about 90°C, more suitably at about 77°C to about 85°C, even more suitably at about 77°C to about 80°C, most suitably at the reflux temperature. The reflux temperature can vary according to the total amount of water. In this process of the present invention, water may be present in the solution in a total amount of about 2 to 6% v/v.

In the above process, precipitation is achieved by cooling the solution to a temperature of at least about 55°C, preferably about 58°C to about 60°C to obtain a suspension. The amount of precipitated crystalline product can be increased by a process comprising at least one of the following steps: cooling the resulting suspension, concentrating the resulting suspension, and further maintaining the second suspension at such temperature for a sufficient period of time, or any combination thereof.

Conveniently, the concentration is carried out at a temperature of about 50°C to about 40°C. Conveniently, the suspension is further maintained at a temperature of about 20°C to about 0°C. Conveniently, the second suspension is maintained for about 10 to about 18 hours, more preferably for about 30 minutes to about 18 hours.

The process for preparing the above crystalline PAL-HCl may further comprise a regeneration process. Said crystalline form can be regenerated by any process known to a person skilled in the art, such as filtration and drying.

Crystalline palonosetron hydrochloride characterized by data selected from the group consisting of: PXRD with reflection peaks at about 12.1, 15.8 and 17.3 ± 0.2 degrees two-theta, PXRD pattern essentially as shown in Figure 2 and combinations thereof, may be prepared by another process comprising exposing crystalline palonosetron hydrochloride characterized by data from the group consisting of: PXRD with reflection peaks at about 13.0, 15.4 and 17.5 ±0.2 degrees two-theta, PXRD layout essentially as shown in Figure 1 and combinations thereof, relative humidity of 100%.

Conveniently, the starting crystalline PAL-HCl is exposed to a relative humidity of 100% at a temperature of about 20°C to about 30°C (room temperature), for a period of about 2 days to about 10 days, preferably about 4 to about 8 days, and more convenient around 7 days.

Starting PAL-HCl for the preparation of any crystalline form of the PAL-HCl of the subject invention can be obtained, for example, according to the procedures described in application No. 11 /...,...(Attorney Docket 13150/48504), which also in the proceedings, filed on October 23, 2007.

The procedure involves reacting Cp 9588 with the following formula,

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with the salt of Cp 9771 of the following formula

[image]

and a base in a mixture of a solvent containing water and an organic solvent immiscible with water to give a free base of Cp 9563 of the following formula,

[image]

regeneration of the free base from Cp 9563; reacting the free base of Cp 9563 with a lithium base, with DMF and with an acid, preferably HCl, to give Cp 9558 of the following formula;

[image]

regeneration Cp 9558; and reacting Cp 9558 in alcohol with no more than 20% hydrogenation catalyst per gram of Cp 9558 to produce a palonosetron salt; wherein HA and HD are each an acid, preferably HCl.

In another process described herein, Cp 9588 is reacted with Cp 9771 to give the salt Cp 9563 of the following formula

[image]

which is reacted with a lithium base, with DMF and with an acid, preferably HCl, to give Cp 9558; and reacting Cp 9558 in alcohol with no more than 20% hydrogenation catalyst per gram of Cp 9558 to give the palonosetron salt, wherein HB is an acid, preferably HCl.

The crystalline forms of the subject invention can be used in a pharmaceutical composition for the treatment and prevention of nausea and vomiting induced by chemotherapy.

The subject invention provides a pharmaceutical composition containing at least one of the palonosetron hydrochloride crystalline forms of the subject invention and a pharmaceutically acceptable excipient.

The present invention also provides a process for preparing a pharmaceutical composition containing at least one of the crystalline forms of palonosetron hydrochloride of the present invention and a pharmaceutically acceptable excipient.

Procedures for administering the pharmaceutical composition of the subject invention include the administration of various preparations, depending on the age, gender and symptoms of the patient. Pharmaceutical compositions can be administered, for example, as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injectable preparations (solutions and suspensions), and the like.

The pharmaceutical compositions of the present invention can optionally be mixed with other forms of palonosetron hydrochloride and/or other active ingredients. In addition, the pharmaceutical compositions of the present invention may contain inactive ingredients such as diluents, carriers, fillers, bulking agents, binders, disintegrators, disintegration inhibitors, absorption accelerators, wetting agents, lubricants, glidants, surfactants, flavoring agents and similar.

Diluents increase the mass of a solid pharmaceutical composition and can create a pharmaceutical dosage form containing the composition that is easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (eg, Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (eg Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol or talc.

Carriers for use in pharmaceutical compositions may include, but are not limited to, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, or silicic acid.

Binders help bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include, for example, acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (eg Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (eg Kollidon®, Plasdon®), pregelatinized starch, sodium alginate or starch.

Disintegrators can enhance dissolution. Disintegrators include, for example, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (eg Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (eg Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrylic potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (eg Explotab®) and starch.

Disintegration inhibitors may include, but are not limited to, white sugar, stearin, peanut butter, hydrogenated oils, and the like.

Absorption accelerators may include, but are not limited to, quaternary ammonium base, sodium lauryl sulfate, and the like.

Wetting agents may include, but are not limited to, glycerin, starch, and the like. Adsorption agents include, but are not limited to, starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like.

A lubricant can be added to the composition to reduce adhesion and facilitate product release from the press or coloring during tableting. Lubricants include, for example, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

Glidants can be added to improve the flowability of uncompacted solids and to improve dosing accuracy. Excipients that can function as glidants include, for example, colloidal silica, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include, for example, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Tablets may further be coated with commonly known coating materials, such as sugar coated tablets, gelatin film coated tablets, enteric release coated tablets, film coated tablets, bilayer tablets and multi-layer tablets. The capsules may be coated with a shell made of, for example, gelatin and optionally containing a plasticizer such as glycerin and sorbitol, and an opacifying or coloring agent.

Solid and liquid compositions may also be colored using any pharmaceutically acceptable dye to improve their appearance and/or facilitate patient identification of the product and dosage unit level.

In the liquid pharmaceutical compositions of the present invention, the palonosetron hydrochloride of the present invention is suspended, while maintaining its crystalline characteristics, and any other solid ingredients are dissolved or suspended in a liquid carrier, such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions may contain emulsifying agents to uniformly disperse the active ingredient or other excipient that is not soluble in the liquid carrier throughout the composition. Emulsifying agents that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus (from a seaweed), pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

The liquid pharmaceutical compositions of the present invention may also contain viscosity-enhancing agents to improve the mouthfeel of the product and/or to coat the mucosa of the gastrointestinal tract. Such agents include, for example, acacia, alginic acid, bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene. carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.

Sweetening agents such as sorbitol, saccharin, saccharin sodium, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve flavor.

Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at safe concentrations to improve storage stability.

The liquid composition according to the present invention may also contain a buffer, such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.

Selection of excipients and amounts to be used can be readily determined by an experienced formulation scientist by reference to standard procedures and reference works known in the art.

The composition for tableting or filling capsules can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are mixed and then further mixed in the presence of a liquid, typically water, which causes the powders to agglomerate into granules. The granulate is sieved and/or ground, dried and then sieved and/or ground to the desired particle size. The granulate may then be tableted or other excipients, such as a glidant and/or lubricant, may be added prior to tableting.

The composition for tableting can be conventionally prepared by dry mixing. For example, a mixed composition of active ingredients and excipients can be compacted into a grain or sheet and then ground into compacted granules. The compacted granules can then be compressed into a tablet.

As an alternative to dry granulation, the blended composition can be compressed directly into a compact dosage form using direct compression techniques. Direct compression gives a more uniform tablet without granules. Excipients particularly well suited to direct tablet compression include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The specific use of these and other excipients in tableting by direct compression is known to experts in the relevant field with experience and expertise for special difficulties in formulating tablets by direct compression.

The filling of the capsules of the subject invention may contain any of the aforementioned mixtures and granulates described with regard to tableting, only if they are not subjected to the final stage of tableting.

When forming a pharmaceutical composition into a pill form, any excipient generally known in the art can be used. For example, carriers include, but are not limited to, lactose, starch, peanut butter, hardened vegetable oil, kaolin, talc, and the like. Binders used include, but are not limited to, gum arabic powder, gum tragacanth powder, gelatin, ethanol, and the like. Disintegration agents used include, but are not limited to, agar, kelp, and the like.

For the purpose of shaping the pharmaceutical composition into suppository form, any excipient generally known in the art can be used. For example, excipients include, but are not limited to, polyethylene glycols, peanut butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like.

When preparing pharmaceutical compositions for injection, solutions and suspensions are sterilized and are conveniently made isotonic with respect to blood. Injectable preparations may use carriers commonly known in the art. For example, carriers for injectable compositions include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. A person of ordinary skill in the art can readily determine with little or no experimentation the amount of sodium chloride, glucose, or glycerin necessary to make an isotonic injectable preparation. Additional ingredients may be added, such as solubilizing agents, buffering agents, and analgesic agents. If necessary, coloring agents, preservatives, fragrances, flavoring agents, sweetening agents and other agents may also be added to the desired compositions during the treatment of schizophrenia.

The amount of palonosetron hydrochloride of the present invention contained in the pharmaceutical composition according to the present invention is not particularly limited; however, the dose should be sufficient to treat, improve, or alleviate the condition.

After discussing the invention with respect to certain preferred embodiments, other embodiments will become apparent to a person skilled in the relevant art from a consideration of this specification. The invention is further defined with reference to the following examples which describe in detail the process and compositions of the invention. It will be apparent to those skilled in the art that many modifications in both materials and methods can be made without departing from the scope of this invention.

EXAMPLES

PXRD method

An ARL powder X-ray diffractometer, model X'TRA-030, Peltier detector, round standard aluminum sample holder with round "zero background quartz plate" was used. The cathode is CuKα radiation, λ = 1.5418 Å. Scanning parameters: Range: 2-40 degrees 2Θ, continuous scanning, speed: 3 degrees/min. The accuracy of the peak position is defined as ±0.2 degrees due to experimental differences, such as instrumentation and sample preparations.

Example 1: Preparation of a crystalline form of PAL-HCl characterized by data selected from the group consisting of: PXRD with peaks at about 13.0, 15.4 and 17.5 degrees two-theta, PXRD pattern essentially as shown in Figure 1 , and combinations thereof.

A solution of about 3.5 g of palonosetron hydrochloride diastereomeric mixture (60.5% 3aS isomer, 39.6%, 3aR isomer) in 90 ml MeOH was concentrated to 12 ml residual volume under vacuum. 38 ml of a mixture of isopropanol-water 97:3 was added at reflux temperature leading to dissolution. The solvent was evaporated at atmospheric pressure to 28 ml residual volume to eliminate most of the remaining MeOH. To the suspension was further added 28 ml of isopropanol-water 97:3 at reflux temperature to achieve complete dissolution. The solution was cooled to 50°C in 100 minutes leading to the initial precipitation of the solid. The mixture was concentrated under vacuum at 50°C until the remaining volume was 34 ml. The suspension was cooled to 20°C in 30 minutes, and after 30 minutes of mixing it was filtered. The solid was dried under nitrogen or vacuum in an oven at 70°C for 10 hours, giving a diastereomeric mixture of crystalline palonosetron HCl of 96% 3aS isomer and 4% 3aR isomer.

Example 2: Preparation of a crystalline form of PAL-HCl characterized by data selected from the group consisting of: PXRD with peaks at about 13.0, 15.4 and 17.5 degrees two-theta, PXRD pattern essentially as shown in Figure 1 , and combinations thereof.

A solution of about 4 g of palonosetron hydrochloride diastereomeric mixture (59.4% 3aS isomer, 40.6% 3aR isomer) in 92 ml MeOH was concentrated to 12 ml residual volume under vacuum. 40 ml of isopropanol was added at reflux temperature. The solvent was evaporated at atmospheric pressure to 32 ml residual volume to eliminate most of the remaining MeOH. 12 ml of isopropanol was further added to the suspension and the mixture was evaporated to 32 ml of the remaining volume. At reflux temperature, 1.6 ml of water was added, resulting in a 95:5 isopropanol-water mixture. A further 4 ml of 95:5 isopropanol-water was added to achieve dissolution at reflux temperature. The solution was cooled to 0°C in 300 minutes (crystallization occurred at 48°C). After 18 hours of stirring at 0°C, the solid was filtered off giving 1.7 g of a diastereomeric mixture of crystalline palonosetron HCl of 96.7% 3aS isomer and 3.3% 3aR isomer.

Example 3: Preparation of a crystalline form of PAL-HCl characterized by data selected from the group consisting of: PXRD with peaks at about 13.0, 15.4 and 17.5 degrees two-theta, PXRD pattern essentially as shown in Figure 1 , and combinations thereof.

A solution of about 4 g of palonosetron hydrochloride diastereomeric mixture (59.4% 3aS isomer, 40.6% 3aR isomer) in 92 ml MeOH was concentrated to 12 ml residual volume under vacuum. 40 ml of isopropanol was added at reflux temperature. The solvent was evaporated at atmospheric pressure to 32 ml residual volume to eliminate most of the remaining MeOH. 12 ml of isopropanol was further added to the suspension, evaporating up to 32 ml of the remaining volume. At reflux temperature, 0.96 ml of water was added, resulting in a 97:3 isopropanol-water mixture. A further 8 ml of 97:3 isopropanol-water was added to achieve dissolution at reflux temperature. The solution was cooled to 0°C in 300 minutes (crystallization occurred at 52°C). After 18 hours of stirring at 0°C, the solid was filtered off giving 1.75 g of a diastereomeric mixture of crystalline palonosetron HCl of 96.1% 3aS isomer and 3.9% 3aR isomer.

Example 4: Preparation of a crystalline form of PAL-HCl characterized by data selected from the group consisting of: PXRD with peaks at about 13.0, 15.4 and 17.5 degrees two-theta, PXRD pattern essentially as shown in Figure 1 , and combinations thereof

A solution of about 4 g of a diastereomeric mixture of palonosetron hydrochloride (63% 3aS isomer, 37% 3aR isomer) in 170 ml MeOH was concentrated under vacuum in a rotary evaporator to a solid residue. 80 ml of isopropanol and 4 ml of water were added and the suspension was heated to reflux temperature. The solvent was evaporated at atmospheric pressure to 32 ml residual volume to eliminate most of the remaining MeOH. 12 ml of isopropanol was further added to the suspension, evaporating up to 32 ml of the remaining volume. At reflux temperature, 0.96 ml of water was added, resulting in a 97:3 isopropanol-water mixture. A further 8 ml of 97:3 isopropanol-water was added to achieve dissolution at reflux temperature. The solution was cooled to 0°C in 300 minutes. After 18 hours of stirring at 0°C, the solid was filtered off giving 1.75 g of a diastereomeric mixture of crystalline palonosetron HCl of 96.1% 3aS isomer and 3.9% 3aR isomer.

Example 5: Preparation of a crystalline form of PAL-HCl characterized by data selected from the group consisting of: PXRD with peaks at about 12.1, 15.8 and 17.3 degrees two-theta, PXRD pattern essentially as shown in Figure 2 , and combinations thereof.

1.1 g of a solid palonosetron hydrochloride diastereomeric mixture (97.7% 3aS isomer, 1.5% 3aR isomer) dried on a filter funnel under nitrogen was suspended in 33 ml of a 95:5 isopropanol-water mixture. The suspension was heated to reflux until dissolved, then cooled to 60°C in 100 minutes leading to crystal formation, then cooled to 40°C in a further 45 minutes, then cooled to 20°C in 30 minutes and stirred at this temperature overnight. . The solid was filtered off and dried for 18 hours at 70°C under nitrogen or vacuum in an oven to give 0.56 g of a diastereomeric mixture of crystalline palonosetron HCl of 99.7% 3aS isomer and 0.3% 3aR isomer.

Example 6: Preparation of a crystalline form of PAL-HCl characterized by data selected from the group consisting of: PXRD with peaks at about 12.1, 15.8 and 17.3 degrees two-theta, PXRD pattern essentially as shown in Figure 2 , and combinations thereof.

1.5 g of a solid palonosetron hydrochloride diastereomeric mixture (96% 3aS isomer, 4%, 3aR isomer) dried on a filter funnel under nitrogen was suspended in 30 ml of a 95:5 isopropanol-water mixture. The suspension was heated to reflux until dissolved, then cooled to 45°C in 60 minutes, then cooled to 20°C in a further 60 minutes, then cooled to 0°C in 30 minutes and stirred at this temperature for 30 minutes. The solid was filtered off and dried for 18 hours at 70°C under nitrogen or vacuum in an oven to give 0.78 g of a diastereomeric mixture of crystalline palonosetron HCl of 99.6% 3aS isomer and 0.4% 3aR isomer.

Example 7: Preparation of a crystalline form of PAL-HCl characterized by data selected from the group consisting of: PXRD with peaks at about 12.1, 15.8 and 17.3 degrees two-theta, PXRD pattern essentially as shown in Figure 2 , and combinations thereof.

3.43 g of a solid palonosetron hydrochloride diastereomeric mixture (99.6% 3aS isomer, 0.4%, 3aR isomer) dried on a filter funnel under nitrogen was suspended in 68 ml of a 95:5 isopropanol-water mixture. The suspension was heated to reflux until dissolved, then cooled to 50°C in 100 minutes (crystal formation was observed at 59°C). The suspension was concentrated to 32 ml residual volume at this temperature under vacuum. The suspension was then cooled to 20°C in 60 minutes, and stirred at this temperature for 60 minutes. The solid was filtered off and dried for 18 hours at 70°C under nitrogen or vacuum in an oven to give 2.6 g of a diastereomeric mixture of crystalline palonosetron HCl of 99.9% 3aS isomer and 0.1% 3aR isomer.

Example 8: Preparation of the free base from Cp 9563 using thionyl chloride

Preparation of Cp 9588:

0.24 g of DMF, 310 ml of toluene and 44.8 g of tetrahydronaphthoic acid at room temperature were charged into a 250 ml glass reactor under a nitrogen atmosphere. The suspension was heated to 51 ±2°C and 32 g of thionyl chloride was added dropwise over about 60 minutes. Addition involves evolution of gas.

The solution was stirred at 51 ± 2°C for 60 minutes. The solvent was then distilled off under reduced pressure at an internal temperature of 46 ±2°C to 210 ml of residual volume (5.1 parts by volume based on tetrahydronaphthoic acid). The thus obtained yellowish acyl chloride solution was used without further purification or isolation in the next step.

Reaction of salts of Cp 9771 and Cp 9588:

29.6 g of NaOH pellets and 50 ml of water were filled into a 1000 ml glass reactor under nitrogen atmosphere. The dissolution is very exothermic. The fluid in the reactor jacket was cooled to maintain an internal temperature of around 60°C. 270 ml of toluene, 42 g of aminoquinuclidine 2HCl were added to the solution at 59 ±2°C. The suspension was stirred at 60 ± 2°C for 60 minutes.

The toluene solution of acyl chloride from step 1 was added dropwise to the suspension at 60 ±2°C over about 1 hour. After 30 minutes, the reaction was considered complete, so 200 ml of water was added.

Then 120 ml of toluene was added. The suspension was stirred at 53 ± 2°C for 30 minutes and then the phases were separated. The aqueous phase was eliminated and the organic phase was washed with 200 ml of a solution of K2CO3 5% in H2O (prepared by dissolving 10 g of K2CO3 in about 190 ml of H2O).

The organic phase is concentrated under reduced pressure at an internal temperature of 55 ±2°C up to 180 ml of the remaining volume.

Example 9: Preparation of Cp 9558 from the free base of Cp 9563

15 g of aminoquinuclidine naphthalene amide and 200 ml of THF at room temperature were filled into a 500 ml glass reactor under nitrogen atmosphere. The solution was cooled to -25 ±2°C.

Keeping the temperature below -15 ±2°C, 54 ml of a solution of hexyl lithium in hexane was added dropwise over 30 minutes.

The purple solution was stirred for 20 minutes at T = -20 ±2°C, then the temperature was lowered to -30 ±2°C and 5.9 g of DMF was added over 30 minutes keeping the temperature below -25°C. The yellowish solution was stirred for 60 minutes at -25 ±2°C. 15 ml of water and 28.5 g of HCl 37% were then added to the solution heated to 0 ±2°C, maintaining the temperature below 15°C. After 40 minutes of mixing, 120 ml of water was added and the mixture was stirred for 20 minutes at room temperature. The phases were then separated and 130 ml of DCM was added to the aqueous phase containing the hydrochloride salt 3-3a of dehydro palonosetron.

28.3 g of NaOH solution 15% w/w was added to the mixture. in water (prepared by dissolving 4.25 g of NaOH pellets in 24 ml of water). The final pH was 10.5.

The layers were separated and 50 ml of a 15% w/w NaCl solution was added to the organic phase. in water (prepared by dissolving 7.5 g of NaCl pellets in about 42.5 ml of water).

The phases were separated and 150 ml of 2-propanol and 6.3 g of HCl 37% were added to the organic phase.

The solvent was distilled off under reduced pressure to 90 ml of the remaining volume with an internal temperature between 35 and 45 °C.

The suspension was heated to 50 ± 2°C and 100 ml of n-heptane was added at this temperature.

The suspension was cooled to 0 ±2°C in 120 minutes, and then after 30 minutes of stirring at this temperature, the solid was filtered by washing the cake with a mixture of 15 ml of IPA and 15 ml of n-heptane, previously cooled to 0 ±2°C.

The solid was dried in an oven under vacuum at 70 ± 2°C for 18 hours, affording 15.0 g of 3-3a dehydro palonosetron HCl. The purity according to HPLC is about 98%.

Example 10: Preparation of palonosetron hydrochloride from Cp 9588 in methanol

A 500 ml glass autoclave was filled with 8 g palonosetron 3-3a dehydro HCl and 150 ml MeOH. 0.8 g of Pd 10% on carbon at 50% humidity was added. It is filled with H2 at 4-5 bar.

The suspension was heated to 50°C and stirred under these conditions for 21 hours (adding H2 while internal pressure <3 bar). The suspension was then cooled to 5 ± 2°C and 2.56 g of a 5% SO2 solution in water was added to quench the reaction.

After 30 minutes of stirring at this temperature, the suspension was filtered through a cake of 10 g of Tecnolite Special 1, washing with 100 ml of MeOH.

The suspension was heated (79°C) until dissolved, then cooled to 0 ±2°C in 300 minutes. After stirring for 30 minutes at 0 ±2°C, the solid was filtered off and the cake was washed with 20 ml of 2-propanol previously cooled to 0 ±2°C. The solid was filtered on a filter funnel for 1 hour.

3 g of moist palonosetron HCl was obtained as a white solid. The purity according to HPLC is about 98.8%.

The wet solid was dried at 70°C for 18 hours under vacuum, affording 2.9 g of palonosetron HCl.

Example 11: Preparation of a crystalline form of PAL-HCl characterized by data selected from the group consisting of: PXRD with peaks at about 12.1, 15.8 and 17.3 degrees two-theta, PXRD pattern essentially as shown in Figure 2 , and combinations thereof.

100 mg of the crystalline form of PAL-HCl characterized by data selected from the group consisting of: PXRD with peaks at about 13.0, 15.4, and 17.5 degrees two-theta, PXRD pattern as shown in Figure 1, and a combination of of that, it was left at 100% relative humidity at room temperature for 1 week. The polymorphic form of the material was measured by X-ray powder diffraction after 1 week of storage.

Example 12: Preparation of a crystalline form of PAL-HCl characterized by data selected from the group consisting of: PXRD with peaks at about 13.0, 15.4 and 17.5 degrees two-theta, PXRD pattern essentially as shown in Figure 1 , and combinations thereof.

5 g of dry palonosetron HCl (99.6% 3aS isomer) was dissolved in 150 g of MeOH at 25°C. The solvent was evaporated on a rotary evaporator at 25°C (bath temperature) to a dry residue. The solid was dried under vacuum at 70°C to give 4.80 g of product.

Claims (48)

1. Crystalline form of palonosetron hydrochloride (PAL-HCl), characterized by data selected from the group consisting of: PXRD (Powder X-Ray Diffraction) with reflection peaks at about 13.0, 15, 4 and 17.5 ±0.2 degrees of two-theta, PXRD patterns as shown in Figure 1 and combinations thereof. 2. The PAL-HCl crystalline form of claim 1, characterized in that it has PXRD with reflection peaks at about 13.0, 15.4 and 17.5 ± 0.2 degrees two-theta. 3. The PAL-HCl crystalline form of any of claims 1 or 2, characterized in that it has a PXRD pattern as shown in Figure 1. 4. A crystalline form of PAL-HCl according to any one of the preceding claims, characterized in that it further has PXRD with reflection peaks at about 7.1, 13.7, 14.2 16.2, 18.5, 20 and 22, 1 ±0.2 degrees two-theta. 5. The crystalline form of PAL-HCl according to any one of the preceding claims, characterized in that the crystalline form has a DSC thermogram with an endothermic peak at about 311°C. 6. The crystalline form of PAL-HCl of any of the preceding claims, characterized in that the crystalline form has a weight loss of less than about 0.1% measured at a temperature of less than or equal to 153°C by TGA. 7. The crystalline form of PAL-HCl according to any one of the preceding claims, characterized in that the crystalline form is the anhydrous form of PAL-HCl. 8. The crystalline form of PAL-HCl of any of the preceding claims, characterized in that the crystalline form has less than 20% of the crystalline form of palonosetron hydrochloride characterized by data selected from the group consisting of: PXRD with reflection peaks at about 12.1, 15.8 and 17.3 ±0.2 degree two-theta, PXRD pattern as shown in Figure 2 and combinations thereof. 9. A process for preparing the crystalline form of PAL-HCl in accordance with any of the preceding claims, characterized in that it comprises crystallization of palonosetron hydrochloride having less than 65% 3aS palonosetron HCl of the following formula, [image] from a solvent selected from the group consisting of: methanol, a mixture of isopropanol (IPA) and water, and a mixture of methanol, isopropanol and water at a temperature below 55°C. 10. The procedure from patent claim 9, characterized in that it consists of: (a) obtaining a solution of PAL-HCl, having less than 65% 3aS palonosetron HCl, in a solvent selected from the group consisting of: methanol, a mixture of isopropanol and water, and a mixture of methanol, isopropanol and water, and (b) precipitating said crystalline PAL-HCl at a temperature below 55°C. 11. The process of claim 10, characterized in that the palonosetron HCl in step (a) has about 50% to about 65% of the 3aS palonosetron HCl isomer. 12. The process of any one of claims 10 or 11, characterized in that the solution of step (a) is prepared by a process consisting of combining PAL-HCl having less than 65% 3aS palonosetron HCl with a solvent at a temperature of about 25 °C to around the reflux temperature. 13. The method of any one of claims 10 to 12, characterized in that the solution of PAL-HCl in methanol is obtained by combining PAL-HCl having less than 65% 3aS palonosetron HCl with methanol at a temperature of about 25°C. 14. The method from any one of claims 10 to 12, characterized in that the PAL-HCl solution in the mixture of IPA and water is obtained by combining PAL-HCl that has less than 65% 3aS palonosetron HCl with the mixture of IPA and water at a temperature of at least 75°C. 15. The method from any one of claims 10 to 12, characterized in that the solution of PAL-HCl in a mixture of methanol, IPA and water is obtained by combining the methanol residue of PAL-HCl that has less than 65% 3aS palonosetron HCl with a mixture of IPA and water at a temperature of at least 75°C. 16. The process of claim 15, characterized in that the methanol residue of PAL-HCl having less than 65% 3aS palonosetron HCl is prepared by a process consisting of: (a) concentrating a PAL-HCl solution having less than 65% 3aS palonosetron HCl in methanol, (b) adding IPA or a mixture of IPA and water to form a mixture, and (c) concentrating the mixture to obtain said methanolic residue. 17. The method of any one of claims 14 to 16, characterized in that the ratio of solvent in the mixture of IPA and water is about 94:6 to about 97:3. 18. The method of claim 17, characterized in that the ratio is from about 95:5 to about 97:3. 19. The method according to any one of claims 14 to 18, characterized in that combining PAL-HCl having less than 65% 3aS palonosetron HCl or its methanol residue with a mixture of IPA and water is carried out at a temperature of about 75°C to about 90°C. 20. The method from any one of claims 14 to 19, characterized in that the solution contains methanol, IPA and water in a ratio of about 0.5:94.5:5, or up to about 0.1:94.9:5 v/v. 21. The method from any one of patent claims 10 to 20, characterized in that the precipitation contains the following stages: (a) cooling the resulting solution, (b) evaporation of the solvent or (c) performing both steps (a) and (b), wherein steps (a)-(c) are carried out at a temperature below 55°C. 22. The method from any one of patent claims 10 to 13, characterized in that the solvent is methanol, and the precipitation is achieved by evaporating the solution at a temperature of about 25°C. 23. The process of any one of claims 10-12 and 14, characterized in that the solvent is a mixture of IPA and water, and the precipitation is achieved by cooling the solution to a temperature below about 55°C to obtain a suspension. 24. The method of claim 23, characterized in that the cooling is to a temperature of about 50°C to about 0°C. 25. The method from any one of patent claims 9 to 24, characterized in that it further contains the regeneration of the obtained crystalline form of PAL-HCl. 26. A crystalline form of PAL-HCl, characterized in that it is characterized by data selected from the group consisting of: PXRD with reflection peaks at about 12.1, 15.8 and 17.3 ±0.2 degrees two-theta, PXRD arrangement as shown in Figure 2 and combinations thereof. 27. The PAL-HCl crystalline form of claim 26, characterized in that it is characterized by PXRD reflection peaks at about 12.1, 15.8 and 17.3 ± 0.2 degrees two-theta. 28. The crystalline form of PAL-HCl according to any one of claims 26 or 27, characterized in that it is characterized by a PXRD pattern as shown in Figure 2. 29. The PAL-HCl crystalline form of any one of claims 26 to 28, further characterized by PXRD reflection peaks at about 7.1, 13.8, 14.2, 14.5, 18.5, 20, 0 and 30.3 ±0.2 degrees two-theta. 30. The crystalline form of PAL-HCl according to any one of claims 26 to 29, characterized in that the crystalline form has a DSC thermogram with an endothermic peak at about 313°C. 31. The crystalline form of PAL-HCl from any one of claims 26 to 30, characterized in that the crystalline form has a weight loss of less than 0.1% measured at a temperature lower than or equal to 152°C by TGA. 32. The crystalline form of PAL-HCl according to any one of claims 26 to 31, characterized in that the crystalline form is the anhydrous form of PAL-HCl. 33. The crystalline form of PAL-HCl according to one of claims 26 to 32, characterized in that the crystalline form has less than 20% of the crystalline form of palonosetron hydrochloride characterized by data selected from the group consisting of: PXRD with reflection peaks at about 13.0 , 15.4 and 17.5 ±0.2 degrees two-theta, PXRD pattern as shown in Figure 1 and combinations thereof. 34. A process for preparing the crystalline form of PAL-HCl according to any one of claims 26 to 33, characterized in that it comprises crystallization of palonosetron hydrochloride having at least 96% 3aS palonosetron HCl of the following formula, [image] from a mixture of isopropanol and water at a temperature above 55°C. 35. The method from patent claim 34, characterized in that the crystallization is performed by a method consisting of (a) obtaining a PAL-HCl solution having less than 96% 3aS palonosetron HCl in a mixture consisting of IPA and water at a temperature above 55°C, and (b) precipitation of said crystalline PAL-HCl by cooling the solution at a temperature of at least about 55°C. 36. The process of claim 35, characterized in that the solution from step (a) is obtained by mixing PAL-HCl having at least 96% 3aS palonosetron HCl with a mixture containing IPA and water to form a suspension, and heating the suspension to temperature above 55°C. 37. The method of any one of claims 34 to 36, characterized in that the solvent ratio in the IPA-water mixture is from about 94:6 to about 98:2. 38. The method of claim 37, characterized in that the solvent ratio in the IPA-water mixture is from about 95:5 to about 98:2. 39. The method from any one of claims 36 to 38, characterized in that the suspension is heated to a temperature of at least 75°C. 40. The method of claim 39, characterized in that the suspension is heated from about 75°C to about 90°C. 41. The method of any one of claims 35 to 40, characterized in that the precipitation is achieved by cooling the solution to a temperature of at least about 55°C to obtain a suspension. 42. The method of claim 41, characterized in that the solution is cooled to a temperature of about 58°C to about 60°C. 43. The method from any one of patent claims 34 to 42, characterized in that it further contains the regeneration of the obtained crystalline form of PAL-HCl. 44. A process for preparing crystalline palonosetron hydrochloride as defined in any of claims 26 to 33, comprising exposing crystalline palonosetron hydrochloride as defined in any of claims 1 to 8 to a relative humidity of about 100%. 45. The method from claim 44, characterized in that exposure is at a temperature of about 20°C to about 30°C. 46. The method according to any one of claims 44 or 45, characterized in that the exposure is for a period of about 2 days to about 10 days. 47. Pharmaceutical composition, characterized in that it contains the crystalline form of palonosetron hydrochloride as defined in any of claims 1 to 8 and/or claims 26 to 33, and a pharmaceutically acceptable excipient. 48. A method for preparing a pharmaceutical composition in accordance with claim 47, characterized in that it contains combining the crystalline form of palonosetron hydrochloride, as defined in any of claims 1 to 8 and/or claims 26 to 33, with a pharmaceutically acceptable excipient .